Amyloid pathways and diseasemodifying treatments for AD: what changes are necessary in new trials? John Hardy

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1 Amyloid pathways and diseasemodifying treatments for AD: what changes are necessary in new trials? John Hardy Reta Lila Weston Research Laboratories Department of Molecular Neuroscience UCL Institute of Neurology London, England

2 The beginning

3 Recombination events in F23 localize the disease locus to a region between S1 and S17 that includes the APP gene

4 7Mb duplication of locus around APP

5 Presenilin With APP in the Active Site APP, amyloid precursor protein, C-TF, carboxy-terminal fragment; DEL, deletion; INS, insertion; N-TF, amino-terminal fragment; PSEN1, presenilin 1.

Precise mechanism of presenilin mutations The mechanism of c-secretase dysfunction in familial Alzheimer disease EMBO ope n Lucia Chávez-Gutiérrez 1,2, Leen Bammens 1,2, Iryna Benilova 1,2, Annelies

6 Precise mechanism of presenilin mutations The mechanism of c-secretase dysfunction in familial Alzheimer disease EMBO ope n Lucia Chávez-Gutiérrez 1,2, Leen Bammens 1,2, Iryna Benilova 1,2, Annelies Vandersteen 3,4, Manasi Benurwar 1,2, Marianne Borgers 1,2, Sam Lismont 1,2, Lujia Zhou 1,2, Simon Van Cleynenbreugel 1,2, Hermann Esselmann 5, Jens Wiltfang 5, Lutgarde Serneels 1,2, Eric Karran 2, Harrie Gijsen 6, Joost Schymkowitz 4,7, Frederic Rousseau 4,7, Kerensa Broersen 3,8 and Bart De Strooper 1,2, * 1 VIB Center for the Biology of Disease, Leuven, Belgium, 2 Center for Human Genetics (CME) and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KUL), Leuven, Belgium, 3 Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, AE Enschede, The Netherlands, 4 Switch Laboratory, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium, 5 Department of Psychiatry and Psychotherapy, LVR-Clinics Essen, University of Duisburg-Essen, Essen, Germany, 6 Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium, 7 VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), Leuven, Belgium and 8 Vrije Universiteit Brussel, Brussel, Belgium

7 Odds ratio ~0.3 Found in AD family but did not segregate Died ischemic stroke age 65

8 AD PS-1/PS-2 mutations APP AD/FTDP-17 - Pathways to neurodegeneration + + APP mutations/ Trisomy 21 Plaques Ab 42? FTDP-17 Tau Dysfunction + tau mutations (FTDP-17) Tangles?? Cell Death Sept. 1998

9 So what is happening in late onset disease? Aβ metabolism Largely work from Washington University, St. Louis group which shows Aβ turnover is reduced in aging. Genetic analysis Many loci now identified most so far are involved in cholesterol metabolism, endosomal vesicle recycling or the innate immune system/microglia activation

10 IGAP Alzheimer analysis ~30,000 cases and ~44,000 controls

11 Other Risk Loci for Alzheimer s Disease Apolipoprotein E4 OR ~4 CLU OR ~1.4 PICALM OR ~1.4 ABCA7 OR ~1.3 CR1 OR ~1.4 Cholesterol metabolism: coding and expression Cholesterol metabolism: complement cascade not coding, not simple expression Endosomal vesicle recycling? Not coding Cholesterol metabolism: not known but Gly1527Ala is possible Complement cascade: very complicated probably sequence and expression BIN1 OR ~1.2 Endosomal vesicle recycling? Not coding MS4A OR ~1.2 Cell surface protein: not coding BIN1, bridging integrator 1; OR, odds ratio. Harold D, et al. Nat Genet. 2009;41: ; Hollingworth P, et al. Nat Genet. 2011;43: ; Lambert JC, et al. Nat Genet. 2009;41:

12 Normal Functioning CR1 and TREM2 Promote Neuroprotection by Microglia

13 Loss of Function of CR1 and TREM2 Promotes Inflammation and Neurotoxicity TNFa, tumor necrosis factor alpha.

14 All genetic data is consistent with the amyloid hypothesis All autosomal genes influence Aβ production Late onset risk loci influence Aβ cleanance Endosomal vesicle cycling.. perhaps APP metabolism. Cholesterol metabolism known to affect Aβ deposition Innate immunity. microglial Aβ clearance

15 Aβ clearance gets less with age

16 What have drug trials taught us? For all the noise, there have only been two shots on target Solenuzemab is hopeful Probably need to treat early. Early diagnosis is difficult CSF tau is best interpreted as a plaque marker (also Jucker mouse work) For later disease, we need to think also of other targets

17 Clear templating of Aβ, tau and SNCA pathology

18 Alzheimer, markers and disease (after Jack)

19 Real data (as well as earlier Down s data from Mann and colleagues) supports Jack model

20 Thus data suggests disease process starts ~20 years before clinical symptoms And that tangle pathology may have an element of being self sustaining Need to treat early (borne out by limited clinical data from some trials). Can genetics help beyond DIAN and ADPI studies?

21 Current predictions for AD Risk: ROC curves of ~0.8: close to utility (Escott- Price et al. Brain: November issue).

22 Summary All genetic data consistent with amyloid hypothesis Clinical data suggests disease process starts a long time before symptoms Animal and other data suggests secondary pathology can become self sustaining ( prion ) Limited clinical data suggests early intervention with Aβ therapies is likely to be important for efficacy Test therapies in APP, PSEN families and in Down syndrome Genetics can help with early diagnosis

Pathways to Alzheimer s disease

Pathways to Alzheimer s disease Key Symposium Click here for more articles from the symposium Watch Guest Editor Professor Mila Kivipelto talk about the 9th Key Symposium: Updating Alzheimer s Disease Diagnosis here. Pathways to Alzheimer